Nonalcoholic fatty liver disease (NAFLD) represents a global health problem. Impaired autophagy has been implicated in the pathogenesis of NAFLD, and CD147 is recognized to regulate lipid metabolism in a variety of cell types. This study was initiated with the aim to identify molecular makers expressed in hepatocytes that are significantly altered during the pathogenesis of NAFLD and closely associated with hepatic steatosis and autophagy. In this study, CD147 was found to be significantly associated with steatosis and autophagy in both clinical patients with NAFLD and NAFLD mouse models. In high-fat-diet-induced NAFLD mice, hepatic-specific CD147 knockout markedly reduced body weight, liver weight, serum aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), and liver steatosis. In addition, hepatic CD147 gene knockout noticeably promoted autophagy in NAFLD mice (LC3 expression was increased with decreased P62 expression; molecular markers of autophagy). Moreover, we found that CD147 expression was significantly associated with AKT/mTOR signaling pathway; thus, suggesting that CD147 is involved in the regulation of autophagy and steatosis in NAFLD. In conclusion, this study has provided in vivo evidence for the putative role of CD147 in the pathogenesis of NAFLD and a valuable experimental basis for considering CD147 as a therapeutic target to prevent hepatic steatosis in patients with NAFLD. (C) 2020 The Author(s). Published by Elsevier Inc.